The major risk factors which are associated with an increased incidence of stroke have been known for many years. However, the basic mechanisms by which these factors lead to the increased risk are not fully understood. Preliminary studies indicate that activation of the immune system by risk factors for stroke increases the risk of endothelial activation and the formation of intravascular thrombosis. By measuring the levels of cytokine and monocyte, macrophage and endothelial cell activation in the stroke- prone population and age-matched controls without risk factors, an attempt will be made to characterize those factors that increase the risk for activation of brain vessel endothelium for a hyperactive inflammatory response to an ischemic insult. In addition, no radiographic findings related to the degree of stenosis for specific morphologic features of the atherosclerotic plaque have been useful in predicting which will become symptomatic and which will remain asymptomatic. In this study, we are analyzing carotid endarterectomy surgical specimens from symptomatic and asymptomatic patients for leukocyte adhesion molecules on the plaque endothelial cells using immunofluorescence staining. Blood drawn at the time of preoperative testing is being examined for leukocyte and endothelial cell activation by fluorescence-activated cell sorting (FACS) and baseline cytokine levels. It is hypothesized that the local release of cytokines and the expression of endothelial cell surface leukocyte receptors play a major role in the conversion of an asymptomatic plaque to a symptomatic one. Understanding the role of cytokines, leukocyte activation, and endothelial interaction in promoting the cerebral ischemic state may lead to a novel approach in future stroke prevention regimens. Our data thus far have revealed that leukocyte activation is significantly elevated in patients with one or more risk factors for stroke as compared to young and age-matched controls. Also, we have demonstrated an increased expression of intercellular adhesion molecule-1 (ICAM- 1) on symptomatic versus asymptomatic patients' atherosclerotic plaques following endarterectomies. Current studies are focusing on genetic regulators of inflammation (i.e., gene polymorphisms in families of cytokines) which may account for the wide variance in leukocyte activation and increased cytokine expression in patients with similar risk factor exposure.